Process for synthesizing oxidized lactam compounds

ABSTRACT

The invention provides a method for the synthesis of dehydrogenated lactam drugs of Formula I:

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/957,694, filed Aug. 2, 2013 which is a divisional of U.S. applicationSer. No. 13/100,515, filed May 4, 2011, now U.S. Pat. No. 8,536,328,issued Sep. 17, 2013, which claims the benefit of U.S. ProvisionalApplication No. 61/331,128, filed on May 4, 2010. The entire teachingsof the above applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

(i) Field of the Invention

The present invention relates to preparation of dehydrogenated lactamdrugs including synthesis of dehydrogenated aripiprazole and cilostazol.

(ii) Background of the Invention

Many of the lactam containing drugs are metabolized to theirdehydrogenated form and are often biologically active. For example,carbostyril derivatives can be metabolized to form dehydrogenatedcarbostyril derivatives. An example of such a drug is aripiprazole whichis metabolized by Cytochrome P450 2D6 (CYP2D6) and CYP3A4 to give theactive metabolite dehydro aripiprazole(7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dehydro-2-(1H)quinolinone). (Kirschbaum et al., The World Journal of BiologicalChemistry, 2008 9(3), 212-8). Satyanarayana et al. recently reported amethod for synthesizing dehydro aripiprazole usingdichlorodicyanoquinone. (Hetercyclic Communications, 2005, 11(6),485-490). However, the procedure reported results in moderate yield(42.5%). While dehydro aripiprazole is commercially available it isexorbitantly expensive. For example, it costs more than $13/mg fromSynFine Research Inc. As such, a more efficient less expensivemethodology is needed to produce dehydro aripiprazole and other oxidizedlactam and carbostyril derivative drugs.

SUMMARY OF THE INVENTION

In part, the invention provides for the synthesis of a compound ofFormula I by the oxidation of Formula IA.

wherein X is —S— or —O—;Each n, m and a is independently selected from 0, 1, 2 or 3;X₁ is selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—,—C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; whereinv is 0, 1, 2, 3, 4, 5;

-   -   wherein each R₁₀ and R₁₁ is independently absent, hydrogen,        halogen, aliphatic, substituted aliphatic, aryl or substituted        aryl; alternatively two R₁₀ and R₁₁ together with the atoms to        which they are attached may form an additional optionally        substituted, 3, 4, 5, 6 or 7 membered ring; and        Each R₁, R₂ and R₃ is independently absent, hydrogen, halogen,        aliphatic, substituted aliphatic, aryl or substituted aryl;        alternatively two or more R₁, R₂ and R₃ together with the atoms        to which they are attached may form one or two additional        optionally substituted, 3, 4, 5, 6 or 7 membered ring; and        Each R_(A), R_(B), R_(C), and R_(D) is independently selected        from hydrogen, halogen, —CN, NR₁₀₀R₁₀₁, wherein said compound of        Formula IA contain a secondary or tertiary amine having a pKa of        about 6 to about 45.

In part, a process for synthesizing oxidized lactam and carbostyrilderivatives is provided. In particular, an efficient method foroxidizing aripiprazole, cilastozol and PF-00217830 to produce theircorresponding dehydrogenated compounds. The dehydrogenation reaction isconducted by the addition of a compound of Formula II to a compound ofFormula IA in the presence of an acid.

DETAILED DESCRIPTION OF THE INVENTION

In part, the invention provides a method for the synthesis of a compoundof Formula I by the oxidation of a compound of Formula IA:

wherein X is —S— or —O—;Each n, m and a is independently selected from 0, 1, 2 or 3;X₁ is selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—,—C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; whereinv is 0, 1, 2, 3, 4, 5;

-   -   wherein each R₁₀ and R₁₁ is independently absent, hydrogen,        halogen, aliphatic, substituted aliphatic, aryl or substituted        aryl; alternatively two R₁₀ and R₁₁ together with the atoms to        which they are attached may form an additional optionally        substituted, 3, 4, 5, 6 or 7 membered ring; and        each R₁, R₂ and R₃ is independently absent, hydrogen, halogen,        aliphatic, substituted aliphatic, aryl or substituted aryl;        alternatively two or more R₁, R₂ and R₃ together with the atoms        to which they are attached may form one or two additional        optionally substituted, 3, 4, 5, 6 or 7 membered ring;        wherein the step of oxidation is comprises the addition of a        compound of Formula II:

wherein each R_(A), R_(B), R_(C), and R_(D) is independently selectedfrom hydrogen, halogen, —CN, NR₁₀₀R₁₀₁, aliphatic, substitutedaliphatic, aryl and substituted aryl; and an acid;wherein said compound of Formula IA contain a primary, secondary ortertiary amine having a pKa of about 6 to about 45.

In another embodiment, the process involves the synthesis of a compoundof Formula III by the oxidation of a compound of Formula IIIA.

wherein, X, R₁, m and n are as defined above;Said compound of Formula IIIA contain a primary, secondary or tertiaryamine having a pKa of about 6 to about 45;The semicircle represents a cyclic moiety containing one, two or threerings;Each R₄ and R₅ is independently absent, hydrogen, halogen, aliphatic,substituted aliphatic, aryl or substituted aryl; alternatively two ormore R₄ and R₅ together with the atoms to which they are attached mayform one or two additional optionally substituted, 3, 4, 5, 6 or 7membered ring;F₁ is selected from absent and R₆-A-Cy₁-B-D-;

-   -   wherein, A is selected from absent, optionally substituted        alkyl, optionally substituted alkenyl, optionally substituted        alkynyl, —S—, —O—, —S(O)—, —S(O)₂—, —S[C(R₁₂)(R₁₃)]_(u)—,        —S(O)[C(R₁₂)(R₁₃)]_(u)—, —S(O)₂[C(R₁₂)(R₁₃)]_(u)—,        —O[C(R₁₂)(R₁₃)]_(u)—, —N(R₁₂)—, —N(R₁₂)[C(R₁₃)(R₁₄)]_(u)—,        —[C(R₁₂)(R₁₃)]_(u), —C(O)[C(R₁₂)(R₁₃)]_(u)—; wherein each R₁₂,        R₁₃ and    -   R₁₄ is independently absent, hydrogen, halogen, aliphatic,        substituted aliphatic, aryl or substituted aryl; wherein each u        is independently 1, 2, 3, 4, 5, 6 or 7;    -   Cy₁ is absent or an optionally substituted cycloalkyl,        optionally substituted cycloalkenyl, optionally substituted        heterocyclyl, optionally substituted aryl or optionally        substituted heteroaryl;    -   B is absent, or a linker;    -   D is selected from absent, —O—, —NR₁₅, —C(R₁₅)(R₁₆)—, —S—,        —S(O)—, —S(O)₂—, —C(O)—;    -   wherein R₁₅, and R₁₆ is independently selected from absent,        hydrogen, halogen, optionally substituted aliphatic, optionally        substituted aryl or optionally substituted heterocyclyl; and        R₆ is independently absent, hydrogen, halogen, aliphatic,        substituted aliphatic, aryl, substituted aryl, heteroaryl,        substituted heteroaryl, heterocyclyl or substituted        heterocyclyl.

In a preferred embodiment, a method for the synthesis of a compound ofFormula IV is provided:

wherein, n, X, F₁, R₁, and R₂ are as defined above;Said compound of Formula IVA contain a primary, secondary or tertiaryamine having a pKa of about 6 to about 45; andX₂ is selected from CH and N.

In a preferred embodiment a method for the synthesis of a compound ofFormula V is provided:

wherein n, X, X₂, R₁, R₂, and R₆ are as defined above;Said compound of Formula VA contain a primary, secondary or tertiaryamine having a pKa of about 6 to about 45; andq is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;R₇ and R₈ are independently selected from absent, hydrogen, halogen,aliphatic, substituted aliphatic, aryl or substituted aryl.

In a preferred embodiment a method for the synthesis of compounds ofFormula VI-XI, is provided where a corresponding compound of FormulaVIA-XIA is oxidized by reacting with a compound of Formula II in thepresence of an acid: In a preferred embodiment, the compound of FormulaII is DDQ and the acid is trifluoroacetic acid.

In a preferred embodiment, the R₆ moiety is an aryl or heteroaryl groupselected from:

wherein R₁₀₀R₁₀₁, and R₁₀₃ are independently selected from hydrogen,halogen, optionally substituted C₁-C₈ alkyl, optionally substitutedC₂-C₈ alkenyl, optionally substituted C₂-C₈ alkynyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted C₁-C₈ alkoxy,optionally substituted C₁-C₈ alkylamino and optionally substituted C₁-C₈aryl.In a preferred embodiment, R₆ is selected from:

In a preferred embodiment, Cy1 is selected from:

In a preferred embodiment, Cy1 is selected from:

In a preferred embodiment, the bivalent B is a direct bond, a straightchain C₁-C₁₀ alkyl, C₁-C₁₀ alkenyl, C₁-C₁₀ alkynyl, C₁-C₁₀ alkoxy,alkoxyC₁-C₁₀alkoxy, C₁-C₁₀ alkylamino, alkoxyC₁-C₁₀alkylamino, C₁-C₁₀alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl, aryloxyC₁-C₁₀alkoxy,aryloxyC₁-C₁₀alkylamino, aryloxyC₁-C₁₀alkylamino carbonyl,C₁-C₁₀-alkylaminoalkylaminocarbonyl, C₁-C₁₀alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino,alkylcarbonylaminoalkylamino, alkyl(N-alkyl)aminoalkylamino,(N-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl,alkylaminoalkylaminoalkyl, alkylpiperazinoalkyl, piperazinoalkyl,alkylpiperazino, alkenylaryloxyC1-C10alkoxy,alkenylarylaminoC₁-C₁₀alkoxy, alkenylaryllalkylaminoC₁-C₁₀alkoxy,alkenylaryloxyC₁-C₁₀alkylamino, alkenylaryloxyC₁-C₁₀alkylaminocarbonyl,piperazinoalkylaryl, heteroarylC₁-C₁₀alkyl, heteroarylC₂-C₁₀alkenyl,heteroarylC₂-C₁₀alkynyl, heteroarylC₁-C₁₀alkylamino,heteroarylC₁-C₁₀alkoxy, heteroaryloxyC₁-C₁₀alkyl,heteroaryloxyC₂-C₁₀alkenyl, heteroaryloxyC₂-C₁₀alkynyl,heteroaryloxyC₁-C₁₀alkylamino and heteroaryloxyC₁-C₁₀alkoxy.

In a preferred embodiment one of R_(A), R_(B), R_(C), and R_(D) isselected from an electron withdrawing group.

In a preferred embodiment, the quinone of Formula II is selected from3,4-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),3,4,5,6-tetrachloro-1,2-benzquinone, ortho-benzoquinone andpara-benzoquinone.

In some embodiments, the acid used in the reaction can be a halogenatedorganic acid. In some embodiments, the halogenated organic acid is afluorinated carboxylic acid. In some embodiments, the acid is selectedfrom trifluroacetic acid, p-toluenesulfonic acid,trifluoromethanesulfonic acid, chlorosulfonic acid, dichloroacetic acid,trichloroacetic acid, acetic acid, propionic acid, sulfuric acid,phosphoric acid, nitric acid, camphorsulfonic acid, hydrochloric acid,oxalic acid, formic acid, propanoic acid, butanoic acid, pentanoic acid,benzoic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid,hydrobromic acid, galuturonic acid, embonic acid, glutamic acid andaspartic acid, glyeonic acid, succinic acid and mixtures thereof.

In some embodiments, said compounds of Formula IA, IIIA, IVA and VAcontain a primary, secondary or tertiary amine moiety having a pKa ofabout 6 to about 45, preferably about 6 to about 30, and preferablyabout 7 to about 20. In some embodiments, the semicircle from FormulaIII and IIIA can be an optionally substituted heterocyclyl, aryl orheteroaryl containing one, two or three rings.

In some embodiments, the reaction is conducted in a solvent selectedfrom tetrahydrofuran, tert-butylmethylether, dimethoxy-ethane, dioxane,benzene, toluene, xylene, dimethylformamide, acetone, acetonitrile,chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-propylacetate, isopropyl acetate, methyl-t-butyl ether, methyl butyl ketoneand combinations thereof.

In a preferred embodiment, R₁ is selected from H, —C(R_(J))(R_(K))—OR₂₀,—C(R_(J))(R_(K))—OC(O)OR₂₀, —C(R_(J))(R_(K))—OC(O)R₂₀,—C(R_(J))(R_(K))—OC(O)NR₂₀R₂₁, —(C(R_(J))(R_(K)))—OPO₃MY,—(C(R_(J))(R_(K)))—OP(O)(OR₂₀)(OR₂₁), —[C(R_(J))(R_(K))O]_(z)—R₂₀,—[C(R_(J))(R_(K))O]_(z)—C(O)OR₂₀, —[C(R_(J))(R_(K))O]_(z)—C(O)R₂₀,—[C(R_(J))(R_(K))O]_(z)—C(O)NR₂₀R₂₁, —[C(R_(J))(R_(K))O]_(z)—OPO₃MY,—[C(R_(J))(R_(K))O]_(z)—P(O)₂(OR₂₀)M and—[C(R_(J))(R_(K))O]_(z)—P(O)(OR₂₀)(OR₂₁);

wherein each R_(J) and R_(K) is independently selected from hydrogen,halogen, aliphatic, substituted aliphatic, aryl or substituted aryl;

each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic,substituted aliphatic, aryl or substituted aryl;

Y and M are the same or different and each is a monovalent cation; or Mand Y together is a divalent cation; and

z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In a preferred embodiment, R₁ is selected from Table-1.

TABLE 1

In a more preferred embodiment, R₁ is selected from Table 2.

TABLE 2

In a more preferred embodiment, R₁ is selected from Table 3.

TABLE 3

In a more preferred embodiment, R₁ is selected from Table 4.

TABLE 4

In a preferred embodiment, a compound of Formula VA selected from TableA is oxidized by reacting with DDQ in the presence of an acid to givethe corresponding dehydrogenated compound of Formula V.

TABLE A No Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

DEFINITIONS

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aliphatic group” or “aliphatic” refers to a non-aromaticmoiety that may be saturated (e.g. single bond) or contain one or moreunits of unsaturation, e.g., double and/or triple bonds. An aliphaticgroup may be straight chained, branched or cyclic, contain carbon,hydrogen or, optionally, one or more heteroatoms and may be substitutedor unsubstituted. In addition to aliphatic hydrocarbon groups, aliphaticgroups include, for example, polyalkoxyalkyls, such as polyalkyleneglycols, polyamines, and polyimines, for example. Such aliphatic groupsmay be further substituted. It is understood that aliphatic groups mayinclude alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, and substituted or unsubstituted cycloalkyl groupsas described herein.

The term “acyl” refers to a carbonyl substituted with hydrogen, alkyl,partially saturated or fully saturated cycloalkyl, partially saturatedor fully saturated heterocycle, aryl, or heteroaryl. For example, acylincludes groups such as (C₁-C₆) alkanoyl (e.g., formyl, acetyl,propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.),(C₃-C₆)cycloalkylcarbonyl (e.g., cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.),heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl,pyrrolid-2-one-5-carbonyl, piperidinylcarbonyl, piperazinylcarbonyl,tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl(e.g., thiophenyl-2-carbonyl, thiophenyl-3-carbonyl, furanyl-2-carbonyl,furanyl-3-carbonyl, 1H-pyrroyl-2-carbonyl, 1H-pyrroyl-3-carbonyl,benzo[b]thiophenyl-2-carbonyl, etc.). In addition, the alkyl,cycloalkyl, heterocycle, aryl and heteroaryl portion of the acyl groupmay be any one of the groups described in the respective definitions.When indicated as being “optionally substituted”, the acyl group may beunsubstituted or optionally substituted with one or more substituents(typically, one to three substituents) independently selected from thegroup of substituents listed below in the definition for “substituted”or the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl portion ofthe acyl group may be substituted as described above in the preferredand more preferred list of substituents, respectively.

The term “alkyl” is intended to include both branched and straightchain, substituted or unsubstituted saturated aliphatic hydrocarbonradicals/groups having the specified number of carbons. Preferred alkylgroups comprise about 1 to about 24 carbon atoms (“C₁-C₂₄”) preferablyabout 7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about24 carbon atoms (“C₈-C₂₄”), preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkyl groups comprise at about 1 to about 8carbon atoms (“C₁-C₈”) such as about 1 to about 6 carbon atoms(“C₁-C₆”), or such as about 1 to about 3 carbon atoms (“C₁-C₃”).Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, n-pentyl,neopentyl and n-hexyl radicals.

The term “alkenyl” refers to linear or branched radicals having at leastone carbon-carbon double bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkenyl radicals are “lower alkenyl”radicals having two to about ten carbon atoms (“C₂-C₁₀”) such asethenyl, allyl, propenyl, butenyl and 4-methylbutenyl. Preferred loweralkenyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”). The terms“alkenyl”, and “lower alkenyl”, embrace radicals having “cis” and“trans” orientations, or alternatively, “E” and “Z” orientations.

The term “alkynyl” refers to linear or branched radicals having at leastone carbon-carbon triple bond. Such radicals preferably contain fromabout two to about twenty-four carbon atoms (“C₂-C₂₄”) preferably about7 to about 24 carbon atoms (“C₇-C₂₄”), preferably about 8 to about 24carbon atoms (“C₈-C₂₄”), and preferably about 9 to about 24 carbon atoms(“C₉-C₂₄”). Other preferred alkynyl radicals are “lower alkynyl”radicals having two to about ten carbon atoms such as propargyl,1-propynyl, 2-propynyl, 1-butyne, 2-butynyl and 1-pentynyl. Preferredlower alkynyl radicals include 2 to about 6 carbon atoms (“C₂-C₆”).

The term “cycloalkyl” refers to saturated carbocyclic radicals havingthree to about twelve carbon atoms (“C₃-C₁₂”). The term “cycloalkyl”embraces saturated carbocyclic radicals having three to about twelvecarbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.

The term “cycloalkenyl” refers to partially unsaturated carbocyclicradicals having three to twelve carbon atoms. Cycloalkenyl radicals thatare partially unsaturated carbocyclic radicals that contain two doublebonds (that may or may not be conjugated) can be called“cycloalkyldienyl”. More preferred cycloalkenyl radicals are “lowercycloalkenyl” radicals having four to about eight carbon atoms. Examplesof such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight chain or branched saturated hydrocarbon chain having thespecified number of carbons atoms. Examples of alkylene groups include,but are not limited to, ethylene, propylene, butylene,3-methyl-pentylene, and 5-ethyl-hexylene.

The term “alkenylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbondouble bond. Alkenylene groups include, but are not limited to, forexample, ethenylene, 2-propenylene, 2-butenylene,1-methyl-2-buten-1-ylene, and the like.

The term “alkynylene,” as used herein, denotes a divalent group derivedfrom a straight chain or branched hydrocarbon moiety containing thespecified number of carbon atoms having at least one carbon-carbontriple bond. Representative alkynylene groups include, but are notlimited to, for example, propynylene, 1-butynylene,2-methyl-3-hexynylene, and the like.

The term “alkoxy” refers to linear or branched oxy-containing radicalseach having alkyl portions of one to about twenty-four carbon atoms or,preferably, one to about twelve carbon atoms. More preferred alkoxyradicals are “lower alkoxy” radicals having one to about ten carbonatoms and more preferably having one to about eight carbon atoms.Examples of such radicals include methoxy, ethoxy, propoxy, butoxy andtert-butoxy.

The term “alkoxyalkyl” refers to alkyl radicals having one or morealkoxy radicals attached to the alkyl radical, that is, to formmonoalkoxyalkyl and dialkoxyalkyl radicals.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one, two or three rings wherein such rings may beattached together in a pendent manner or may be fused. The term “aryl”embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl,indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo”refer to saturated, partially unsaturated and unsaturatedheteroatom-containing ring-shaped radicals, which can also be called“heterocyclyl”, “heterocycloalkenyl” and “heteroaryl” correspondingly,where the heteroatoms may be selected from nitrogen, sulfur and oxygen.Examples of saturated heterocyclyl radicals include saturated 3 to6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e.g.pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.); saturated3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms (e.g. morpholinyl, etc.); saturated 3 to6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1to 3 nitrogen atoms (e.g., thiazolidinyl, etc.). Examples of partiallyunsaturated heterocyclyl radicals include dihydrothiophene,dihydropyran, dihydrofuran and dihydrothiazole. Heterocyclyl radicalsmay include a tetravalent nitrogen, such as in tetrazolium andpyridinium radicals. The term “heterocycle” also embraces radicals whereheterocyclyl radicals are fused with aryl or cycloalkyl radicals.Examples of such fused bicyclic radicals include benzofuran,benzothiophene, and the like.

The term “heteroaryl” refers to unsaturated aromatic heterocyclylradicals. Examples of heteroaryl radicals include unsaturated 3 to 6membered heteromonocyclic group containing 1 to 4 nitrogen atoms, forexample, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g.1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensedheterocyclyl group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g.,tetrazolo[1,5-b]pyridazinyl, etc.), etc.; unsaturated 3 to 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groupcontaining a sulfur atom, for example, thienyl, etc.; unsaturated 3- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.)etc.; unsaturated condensed heterocyclyl group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl,etc.); unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl (e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g.,benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term “heterocycloalkyl” refers to heterocyclo-substituted alkylradicals. More preferred heterocycloalkyl radicals are “lowerheterocycloalkyl” radicals having one to six carbon atoms in theheterocyclo radical.

The term “alkylthio” refers to radicals containing a linear or branchedalkyl radical, of one to about ten carbon atoms attached to a divalentsulfur atom. Preferred alkylthio radicals have alkyl radicals of one toabout twenty-four carbon atoms or, preferably, one to about twelvecarbon atoms. More preferred alkylthio radicals have alkyl radicalswhich are “lower alkylthio” radicals having one to about ten carbonatoms. Most preferred are alkylthio radicals having lower alkyl radicalsof one to about eight carbon atoms. Examples of such lower alkylthioradicals include methylthio, ethylthio, propylthio, butylthio andhexylthio.

The terms “aralkyl” or “arylalkyl” refer to aryl-substituted alkylradicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl,and diphenylethyl.

The term “aryloxy” refers to aryl radicals attached through an oxygenatom to other radicals.

The terms “aralkoxy” or “arylalkoxy” refer to aralkyl radicals attachedthrough an oxygen atom to other radicals.

The term “aminoalkyl” refers to alkyl radicals substituted with aminoradicals. Preferred aminoalkyl radicals have alkyl radicals having aboutone to about twenty-four carbon atoms or, preferably, one to abouttwelve carbon atoms. More preferred aminoalkyl radicals are “loweraminoalkyl” that have alkyl radicals having one to about ten carbonatoms. Most preferred are aminoalkyl radicals having lower alkylradicals having one to eight carbon atoms. Examples of such radicalsinclude aminomethyl, aminoethyl, and the like.

The term “alkylamino” denotes amino groups which are substituted withone or two alkyl radicals. Preferred alkylamino radicals have alkylradicals having about one to about twenty carbon atoms or, preferably,one to about twelve carbon atoms. More preferred alkylamino radicals are“lower alkylamino” that have alkyl radicals having one to about tencarbon atoms. Most preferred are alkylamino radicals having lower alkylradicals having one to about eight carbon atoms. Suitable loweralkylamino may be monosubstituted N-alkylamino or disubstitutedN,N-alkylamino, such as N-methylamino, N-ethylamino, N,N-dimethylamino,N,N-diethylamino or the like.

The term “substituted” refers to the replacement of one or more hydrogenradicals in a given structure with the radical of a specifiedsubstituent including, but not limited to: halo, alkyl, alkenyl,alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl,arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl,alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl,arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino,trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl,arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl,alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl,carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl,heteroaryl, heterocyclic, and aliphatic. It is understood that thesubstituent may be further substituted.

For simplicity, chemical moieties that are defined and referred tothroughout can be univalent chemical moieties (e.g., alkyl, aryl, etc.)or multivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, an “alkyl” moiety can bereferred to a monovalent radical (e.g. CH₃—CH₂—), or in other instances,a bivalent linking moiety can be “alkyl,” in which case those skilled inthe art will understand the alkyl to be a divalent radical (e.g.,—CH₂—CH₂—), which is equivalent to the term “alkylene.” Similarly, incircumstances in which divalent moieties are required and are stated asbeing “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”,“heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”,or “cycloalkyl”, those skilled in the art will understand that the termsalkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, “aryl”, “heteroaryl”,“heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or“cycloalkyl” refer to the corresponding divalent moiety.

The terms “halogen” or “halo” as used herein, refers to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The terms “compound” “drug”, and “prodrug” as used herein all includepharmaceutically acceptable salts, co-crystals, solvates, hydrates,polymorphs, enantiomers, diastereoisomers, racemates and the like of thecompounds, drugs and prodrugs having the Formulas as set forth herein.

Substituents indicated as attached through variable points ofattachments can be attached to any available position on the ringstructure.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, Formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims. General methodology forthe preparation of lactam compounds can be found in the followingpublications: U.S. Pat. No. 7,160,888; U.S. Pat. No. 5,462,934; U.S.Pat. No. 4,914,094; U.S. Pat. No. 4,234,584; U.S. Pat. No. 4,514,401;U.S. Pat. No. 5,462,934; U.S. Pat. No. 4,468,402; WO 2006/090273 A2; WO2008/150848 A1; WO 2006/112464 A1; WO 2008/132600 A1.

Example 1 Large Scale Synthesis of dehydroaripiprazole[7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)quinolin-2(1H)-one](Compound 1; Formula VI)

Aripiprazole (Formula VIA; 15 g, 0.03 mol) was dissolved in anhydroustetrahydrofuran (360 mL). Trifluoroacetic acid (12 mL, 0.16 mol) wasadded to the clear solution. 1,2-Dichloro-4,5-dicyano quinone (24.3 g,0.11 mol) was added and the mixture was stirred at room temperatureunder nitrogen atmosphere. The reaction was stirred for 40 minutes andTLC showed no starting material remaining Water (1.5 L) was added thenreaction mixture basified with 50% aq NaOH until pH 12. The reactionmixture was extracted with dichloromethane (3×1 L) and the combinedorganics were dried (MgSO₄) to give the crude product. This was purifiedby column chromatography on silica eluting with dichloromethane to 10%methanol/dichloromethane. The product was further purified byrecrystallisation from 2-propanol to give the desired product (13.7 g,92%) as an off white solid. ¹H-NMR (400 MHz, CDCl₃) δ 12.33 (1H, br s),7.72 (1H, d), 7.42 (1H, d), 7.16-7.11 (2H, m), 6.98-6.93 (1H, dd),6.83-6.79 (2H, m), 6.53 (1H, d), 4.10 (2H, t), 3.09 (4H, br s), 2.67(4H, br s), 2.52 (2H, t), 1.93-1.70 (4H, m). LCMS (acidic method) [M+H]⁺446.02, rt 14.246 min.

Example 2 Synthesis of(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylbutyrate (Compound 2)

Step 1: Preparation of7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-1-(hydroxymethyl)-3,4-dihydroquinolin-2(1H)-one(Compound 2A)

A mixture of Aripiprazole (20 g, 45 mmol), triethylamine (1 mL, 7.1mmol), formaldehyde (37% aqueous solution, 70 mL) and dimethylformamide(200 mL) was heated to 80° C. for 20 h. The reaction mixture was cooled,diluted with ethyl acetate (400 mL) and washed with water/brine (1:1,3×500 mL). The organic phase was dried over MgSO₄, filtered andevaporated to dryness under vacuum to give hemi-aminal Compound 2A as awhite solid (18.6 g, containing 25% Aripiprazole, 65% yield based on2A).

Step 2: Synthesis of(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)methylbutyrate (Compound 2B)

To a stirred suspension of Compound 2A (3 g, 6.27 mmol) indichloromethane (30 mL) was added pyridine (2.54 mL, 31.35 mmol)followed by butyryl chloride (0.98 mL, 9.41 mmol) over 1-2 mins. Theresultant solution was stirred at room temperature for 1 h 30 mins. Thereaction was quenched with methanol (2 mL) and the mixture diluted with1:1 NaHCO₃ (aq)/brine (50 mL) and the layers separated. The aqueouslayer was extracted with dichloromethane (10 mL) and the combinedorganics dried over MgSO₄. After filtration, the volatiles were removedand the residue azeotroped with toluene (3×10 mL). The crude materialwas purified by silica chromatography eluting 8% Methanol/(1:1 ethylacetate/dichloromethane) to provide the desired product, Compound 2B(3.26 g, 5.94 mmol, 95% yield).

Step 3: Synthesis of Compound 2

To a stirred solution of Compound 2B (3.26 g, 5.94 mmol) in THF (100 mL)was added TFA (2.74 mL, 35.63 mmol) followed by DDQ (7.01 g, 30.88 mmol)in THF (40 mL). The reaction was stirred at room temperature over theweekend. The reaction was quenched with water (100 mL) and then pouredinto water (600 mL) and dichloromethane (100 mL). Solid NaHCO₃ (100 g)was added and the mixture stirred for approximately 30 minutes.Dichloromethane (200 mL) was added and the mixture filtered. Thecollected filtrate was transferred to a separating funnel and the layersseparated. The aqueous layer was extracted with dichloromethane (2×100mL) and the combined organics washed with water (3×100 mL, brine (100mL) and dried over MgSO₄. After filtration, the volatiles were removed.The crude material was purified by silica chromatography eluting 0-4%Methanol/(1:1 ethyl acetate/dichloromethane). The oil was recrystallizedfrom methanol to give Compound 2, (2.03 g, 3.72 mmol, 63% yield). ¹H-NMR(300 MHz, CDCl₃) δ 7.63 (1H, d), 7.45 (1H, d), 7.19-7.06 (2H, m),6.99-6.90 (1H, m), 6.88-6.78 (2H, m), 6.52 (1H, d), 6.33 (2H, s), 4.06(2H, t), 3.17-2.99 (4H, bs), 2.74-2.43 (6H, m), 2.35 (2H, t), 1.94-1.54(6H, m), 0.93 (3H, t).

The following compounds were prepared in an analogous fashion toCompound 2:

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylpalmitate (Compound 3)

¹H-NMR (400 MHz, CDCl₃) δ 7.62 (1H, d), 7.44 (1H, d), 7.18-7.10 (2H, m),6.98-6.91 (1H, m), 6.87-6.80 (2H, m), 6.52 (1H, d), 6.32 (2H, s), 4.05(2H, t), 3.15-2.99 (4H, bs), 2.74-2.44 (6H, m), 2.35 (2H, t), 1.92-1.83(2H, m), 1.80-1.68 (2H, m) 1.66-1.55 (2H, m), 1.32-1.14 (24H, m), 0.87(3H, t).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyllaurate (Compound 4)

¹H-NMR (400 MHz, CDCl₃) δ 7.62 (1H, d), 7.43 (1H, d), 7.17-7.10 (2H, m),6.96-6.92 (1H, m), 6.87-6.80 (2H, m), 6.51 (1H, d), 6.33 (2H, s), 4.06(2H, t), 3.12-3.01 (4H, bs), 2.71-2.59 (4H, bs), 2.50 (2H, t), 2.35 (2H,t), 1.92-1.83 (2H, m), 1.78-1.69 (2H, m) 1.66-1.55 (2H, m), 1.32-1.16(16H, m), 0.86 (3H, t).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylstearate (Compound 5)

¹H-NMR (400 MHz, CDCl₃) δ 7.62 (1H, d), 7.44 (1H, d), 7.17-7.11 (2H, m),6.97-6.92 (1H, m), 6.87-6.79 (2H, m), 6.51 (1H, d), 6.32 (2H, s), 4.05(2H, t), 3.13-3.00 (4H, bs), 2.73-2.58 (4H, bs), 2.50 (2H, t), 2.35 (2H,t), 1.92-1.83 (2H, m), 1.79-1.69 (2H, m) 1.66-1.55 (2H, m), 1.32-1.14(28H, m), 0.87 (3H, t).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methylacetate (Compound 6)

¹H-NMR (300 MHz, CDCl₃) δ 7.63 (1H, d), 7.45 (1H, d), 7.18-7.11 (2H, m),6.98-6.92 (1H, m), 6.90-6.80 (2H, m), 6.52 (1H, d), 6.32 (2H, s), 4.07(2H, t), 3.14-3.01 (4H, bs), 2.73-2.59 (4H, bs), 2.51 (2H, t), 2.12 (3H,s), 1.95-1.82 (2H, m), 1.82-1.68 (2H, m).

(7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxoquinolin-1(2H)-yl)methyl2,2-dimethylbutanoate (Compound 7)

¹H-NMR (400 MHz, CDCl₃) δ 7.61 (1H, d), 7.43 (1H, d), 7.17-7.10 (2H, m),6.97-6.92 (1H, m), 6.83-6.79 (2H, m), 6.51 (1H, d), 6.31 (2H, s), 4.05(2H, t), 3.12-3.02 (4H, bs), 2.71-2.60 (4H, bs), 2.50 (2H, t), 1.92-1.83(2H, m), 1.78-1.68 (2H, m) 1.55 (2H, q), 1.15 (6H, s), 0.81 (3H, t).

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. All other published references, documents,manuscripts and scientific literature cited herein are herebyincorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

What is claimed:
 1. A method for preparing a compound of Formula I, comprising the step of reacting a compound of Formula IA:

with a compound selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and para-benzoquinone in the presence of an acid; wherein X is —S— or —O—; each n, m and a is independently selected from 0, 1, 2 or 3; X₁ is selected from absent, —S—, —O—, —S(O)—, —S(O)₂—, —N(R₁₀)—, —C(O)—, —C(OR₁₀)(R₁₁)—, —[C(R₁₀)(R₁₁)]_(v)—, —C(R₁₀)(R₁₁)═C(R₁₀)(R₁₁)—; wherein v is 0, 1, 2, 3, 4, 5; wherein each R₁₀ and R₁₁ is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two R₁₀ and R₁₁ together with the atoms to which they are attached may form an additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; each R₁, R₂ and R₃ is independently absent, hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; alternatively two or more R₁, R₂ and R₃ together with the atoms to which they are attached may form one or two additional optionally substituted, 3, 4, 5, 6 or 7 membered ring; and wherein said compound of Formula IA contains a primary, secondary or tertiary amine having a pKa of about 6 to about
 45. 2. The method according to claim 1, wherein R₁ is selected from H, —C(R_(J))(R_(K))—OR₂₀, —C(R_(J))(R_(K))—OC(O)OR₂₀, —C(R_(J))(R_(K))—OC(O)R₂₀, —C(R_(J))(R_(K))—OC(O)NR₂₀R₂₁, —(C(R_(J))(R_(K)))—OPO₃MY, —(C(R_(J))(R_(K)))—OP(O)(OR₂₀)(OR₂₁), —[C(R_(J))(R_(K))O]_(z)—R₂₀, —[C(R_(J))(R_(K))O]_(z)—C(O)OR₂₀, —[C(R_(J))(R_(K))O]_(z)—C(O)R₂₀, —[C(R_(J))(R_(K))O]_(z)—C(O)NR₂₀R₂₁, —[C(R_(J))(R_(K))O]_(z)—OPO₃MY, —[C(R_(J))(R_(K))O]_(z)—P(O)₂(OR₂₀)M and —[C(R_(J))(R_(K))O]_(z)—P(O)(OR₂₀)(OR₂₁); wherein: each R_(J) and R_(K) is independently selected from hydrogen, halogen, aliphatic, substituted aliphatic, aryl or substituted aryl; each R₂₀ and R₂₁ is independently selected from hydrogen, aliphatic, substituted aliphatic, aryl or substituted aryl; Y and M are the same or different and each is a monovalent cation; or M and Y together is a divalent cation; and z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or
 10. 3. A method according to claim 2, wherein R₁ is selected from Tables 1-4: TABLE 1

TABLE 2

TABLE 3

TABLE 4


4. The method according to claim 1, wherein said acid is selected from trifluroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, dichloroacetic acid, trichloroacetic acid, acetic acid, propionic acid, sulfuric acid, phosphoric acid, nitric acid, camphorsulfonic acid, hydrochloric acid, oxalic acid, formic acid, propanoic acid, butanoic acid, pentanoic acid, benzoic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, hydrobromic acid, and mixtures thereof.
 5. The method according to claim 4, wherein said acid is trifluroacetic acid.
 6. The method according to claim 1, wherein the reaction is conducted in a solvent selected from tetrahydrofuran, tert-butylmethylether, dimethoxy-ethane, dioxane, benzene, toluene, xylene, dimethylformamide, acetone, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, methyl-t-butyl ether, methyl butyl ketone and combinations thereof.
 7. The method according to claim 1, wherein said pKa range of primary, secondary or tertiary amine is between about 6 to about
 30. 8. A method for preparing a compound of Formula VI, comprising the step of reacting a compound of Formula VIA with a compound selected from 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and para-benzoquinone in the presence of an acid:


9. The method according to claim 8, wherein said acid is selected from trifluroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, chlorosulfonic acid, dichloroacetic acid, trichloroacetic acid, acetic acid, propionic acid, sulfuric acid, phosphoric acid, nitric acid, camphorsulfonic acid, hydrochloric acid, oxalic acid, formic acid, propanoic acid, butanoic acid, pentanoic acid, benzoic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, citric acid, ascorbic acid, tartaric acid, maleic acid, and hydrobromic acid, and mixtures thereof.
 10. The method according to claim 9, wherein said acid is trifluroacetic acid.
 11. The method according to claim 8, wherein the reaction is conducted in a solvent selected from tetrahydrofuran, tert-butylmethylether, dimethoxy-ethane, dioxane, benzene, toluene, xylene, dimethylformamide, acetone, acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, methyl-t-butyl ether, methyl butyl ketone and combinations thereof. 